title: IRE1α dissociates with BiP and inhibits ER stress-mediated apoptosis in cartilage development.
abstract: Bone morphogenetic protein 2 is known to activate unfolded protein response signaling molecules, including XBP1S, BiP and IRE1α. Endoplasmic reticulum stress is induced in chondrogenesis and activates IRE1α signal pathway, which is associated with ER stress-mediated apoptosis. However, the influence on IRE1α and BiP in BMP2-induced chondrocyte differentiation has not yet been elucidated; the molecular mechanism remains unexplored. In this study, we demonstrate that IRE1α interacts with BiP in unstressed cells and dissociates from BiP in the course of cartilage development. Induction of ER stress-responsive proteins (XBP1S, IRE1α, BiP) was also observed in differentiating cells. IRE1α inhibition ER stress-mediated apoptosis lies in the process of chondrocyte differentiation. Furthermore, knockdown of IRE1α expression by way of the RNAi approach accelerates ER stress-mediated apoptosis in chondrocyte differentiation induced by BMP2, as revealed by enhanced expressions of cleaved caspase3, CHOP and p-JNK1; and this IRE1α inhibition effect on ER stress-mediated apoptosis is required for BiP in chondrogenesis. Collectively, the ER stress sensors were activated during apoptosis in cartilage development, suggesting that selective activation of ER stress signaling was sufficient for induction of apoptosis. These findings reveal a novel critical role of IRE1α in ER stress-mediated apoptosis and the molecular mechanisms involved. These results suggest that activation of p-JNK1, caspase3 and CHOP was detected in developing chondrocytes and that specific ER stress signaling leads to naturally occurring apoptosis during cartilage development.
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhou
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Song
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Meiling
authors.initials: M
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Xia
authors.forename: Feng-Jin
authors.initials: FJ
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D020219:Chondrogenesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8; D004722:Endoribonucleases; D053148:Caspase 3
keywords: ATF6; Apoptosis; BMP2; BiP; Cartilage development; Endoplasmic reticulum stress; IRE1α; PERK; PKR-like ER resistant kinase; UPR; X-box binding protein1 spliced; XBP1S; activating transcription factor 6; binding immunoglobulin protein; bone morphogenetic protein 2; inositol requiring enzyme 1α; unfolded protein response